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Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice

Nature Genetics volume 16, pages 19–27 (1997)Cite this article

Abstract

Targeted mutagenesis in mice, a powerful tool for the analysis of gene function and human disease, makes extensive use of 129 mouse substrains. Although all are named 129, we document that outcrossing of these substrains, both deliberate and accidental, has lead to extensive genetic variability among substrains and embryonic stem cells derived from them. This clearer understanding of 129 substrain variability allows consideration of its negative impact on targeting technology, including: homologous recombination frequencies, preparation of inbred animals, and availability of appropriate controls. Based on these considerations we suggest a number of recommendations for future experimental design.

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References

  1. Deng, C. & Capecchi, M.R. Reexamination of Gene Targeting Frequency as a Function of the Extent of Homology between the Targeting Vector and the Target Locus. Mol. Cell.Biol. 12, 3365–3371 (1992).

    Article  CAS  Google Scholar 

  2. Festing, M.F.W. Inbred strains of mice. Mouse Genome 94, 523–677 (1996).

    Google Scholar 

  3. Stevens, L.C. A new inbred subline of mice (129/terSv) with a high incidence of spontaneous congenital testicular teratomas. J. Natl. CancerInst. 50, 235–242 (1973).

    Article  CAS  Google Scholar 

  4. Stevens, L.C. Spontaneous testicular teratomas in an inbred strain of mice. Proc. Natl. Acad. Sci. USA 40, 1080–1087 (1954).

    Article  CAS  Google Scholar 

  5. Stevens, L.C. & Hummel, K.P. A description of spontaneous congenital testicular teratomas in strain 129 mice. J. Natl. Cancer Inst. 18, 719–747 (1957).

    CAS  PubMed  Google Scholar 

  6. Kuehn, M.R., Bradley, A., Robertson, E.J. & Evans, M.J. A potential animal model for Lesch-Nyhan syndrome through introduction of HPRT mutations into mice. Nature 326, 295–301(1987).

    Article  CAS  Google Scholar 

  7. Asada, Y Varnum, D.S., Frankel, W.N. & Nadeau, J.H. A potential animal modelfor Lesch-Nyhan syndrome through introduction of HPRT mutations into mice. Nature 363–368 (1994).

  8. Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured. Nature 326, 292–295 (1987).

    Article  CAS  Google Scholar 

  9. Magin, T.M., McWhir, J. & Melton, D.W. A new mouse embryonic stem cell line with good germ line contribution and gene targeting frequency. Nucl. Acids Res. 20, 3795–3796 (1992).

    Article  CAS  Google Scholar 

  10. Knudson, C.M., Tung, K.S., Tourtellotte, W.G., Brown, G.A. & Korsmeyer, S.J. Baxdeficient mice with lymphoid hyperplasia and male germ cell death. Science 270, 96–99 (1995).

    Article  CAS  Google Scholar 

  11. Shipley, J.M., Wesselschmidt, R.L., Kobayashi, D.K., Shapiro, S.D Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Natl. Acad. Sci. USA 93, 3942–3946 (1996).

    Article  CAS  Google Scholar 

  12. Doetschman, T.C., Eistetter, H., Katz, M., Schmidt, W. & Kemler, R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood island and myocardium. J. Embryol. Exp. Morph. 87, 27–45 (1985).

    CAS  PubMed  Google Scholar 

  13. Robertson, E., Bradley, A., Kuehn, M. & Evans, M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature 323, 445–448 (1986).

    Article  CAS  Google Scholar 

  14. McMahon, A.P. & Bradley, A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell. 62, 1073–1085 (1990).

    Article  CAS  Google Scholar 

  15. Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 64, 693–702 (1991).

    Article  CAS  Google Scholar 

  16. Li, E., Bestor, T. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 69, 915–926 (1992).

    Article  CAS  Google Scholar 

  17. Nagy, A., Rossant, J., Nagy, R., Abramownewerly, W. & Roder, J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl. Acad. Sci. USA 90, 8424–8428 (1993).

    Article  CAS  Google Scholar 

  18. Schwartzberg, P.L., Goff, S.P. & Robertson, E.J. Germ-line transmission of a c-abl mutation produced by targeted gene disruption of ES cells. Science. 246, 799–803 (1989).

    Article  CAS  Google Scholar 

  19. Bailey, D.W. Four approaches to estimating the number of histocompatibility loci in mice. Transplant Proc.. 2, 32–38 (1970).

    CAS  PubMed  Google Scholar 

  20. Bailey, D.W. How pure are inbred strains of mice? Immun. Today. 3, 210–214 (1982).

    Article  CAS  Google Scholar 

  21. Stevens, L.C., Mouse News Letter (companion issue Inbred Strains of Mice) 61, 38–39 (1979).

  22. Bultman, S.J. et al. Molecular analysis of reverse mutations from nonagouti (a) to black-and-tan (at) and white-bellied agouti (AW) reveals alternative forms of agouti transcripts. Genes Dev. 8, 481–490 (1994).

    Article  CAS  Google Scholar 

  23. Stevens, L.C., Mouse News Letter (Companion Issue Inbred Strains of Mice). 57, 35–36 (1977).

    Google Scholar 

  24. Dietrich, W.F. et al. A comprehensive genetic map of the mouse genome. Nature 380, 149–152 (1996).

    Article  CAS  Google Scholar 

  25. Silver, L.M. Mouse genetics: concepts and applications 1–362 (Oxford University Press, New York 1995).

    Google Scholar 

  26. Mouse Genome Database. Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, Maine. World Wide Web (URL: http://www. informatics.jax.org/) (Oct. 1996).

  27. Wehner, J.M. & Silva, A. Importance of strain differences in evaluations of learning and memory processes in null mutants. Ment. Retard. Dev. Disabil. 4, 1–6 (1996).

    Google Scholar 

  28. Sadlack, B. et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25, 3053–3059 (1995).

    Article  CAS  Google Scholar 

  29. Sibilia, M. & Wagner, E.F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238 (1995).

    Article  CAS  Google Scholar 

  30. Threadgill, D.W. et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269, 230–234 (1995).

    Article  CAS  Google Scholar 

  31. Skarnes, W.C., Auerbach, B.A. & Joyner, A.L. A gene trap approach in mouse embryonic stem cells: the lacZ reported is activated by splicing, reflects endogenous gene expression, and is mutagenic in mice. Genes Dev.. 6, 903–918 (1992).

    Article  CAS  Google Scholar 

  32. Zuberi, A.R., Christianson, G.J. & Roopenian, D.C. Allele sizes at Chromosome 2 Mit loci from 129/J, 129/Ola, C57BL/10J, and the autoimmune-prone mouse strains BXSB/MpJ-Vaa, MRL/MpJ, SJL/J and NZB/B1NJ. Mouse Genome 94, 152–154 (1996).

    Google Scholar 

  33. Matouk, C., Gosselin, D., Malo, D., Skamene, E. & Radzioch, D. PCR-analyzed microsatellites for the inbred mouse strain 129/Sv, the strain most commonly used in gene knockout technology. Mamm. Genome 7, 603–605 (1996).

    Article  CAS  Google Scholar 

  34. Dietrich, W.F. A complete genetic map of the mouse and its application to the study of mouse models of human disease 1–219 (Massachusetts Institute of Technology, Cambridge, 1993).

  35. Kontgen, F., Suss, G., Stewart, C., Steinmetz, M. & Bluethmann, H. Targeted Disruption of the MHC class-ll Aa Gene in C57BL/6 Mice. Int. Immunol. 5, 957–964 (1993).

    Article  CAS  Google Scholar 

  36. Ledermann, B. & Burki, K. Establishment of a germ-line competent C57BL/6 embryonic stem cell line.. Exp. Cell Res. 197, 254–258 (1991).

    Article  CAS  Google Scholar 

  37. Kawase, E. et al. Strain difference in establishment of mouse embryonic stem (ES) cell lines. Int. J. Dev. Biol. 38, 385–90 (1994).

    CAS  PubMed  Google Scholar 

  38. McWhir, J. et al. Selective ablation of differentiated cells permits cell lines from murine embryos with a non-permissive genetic background. Nature Genet. 14, 223–226 (1996).

    Article  CAS  Google Scholar 

  39. Esaki, K & Takeshi, T ICLAS Manual for genetic monitoring of inbred mice 1-187 (Univeristy of Tokyo Press, Tokyo, 1984).

  40. Sagai, T & Moriwaki, K A simplified micro-method for cytotoxicity testing using a flat-type titration plate for the detection of H-2 antigens. Microbiol. Immunol. 25, 1327–1234 (1981).

    Google Scholar 

  41. Bailey, D.W. & Usama, B. A rapid method of grafting skin on tails of mice. plast. Reconstr. Surg. Transplant.Bull. 25, 424–425 (1960).

    Article  Google Scholar 

  42. Silvers, W.K. The coat colors of mice 1–379 (Springer-Verlag, New York, 1979).

    Chapter  Google Scholar 

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Authors and Affiliations

  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, USA

    Elizabeth M. Simpson, Carol C. Linder, Evelyn E. Sargent, Muriel T. Davisson, Larry E. Mobraaten & John J. Sharp

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Simpson, E., Linder, C., Sargent, E. et al. Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nat Genet 16, 19–27 (1997). https://doi.org/10.1038/ng0597-19

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